Thyroid hormone (TH) plays a critical role in differentiation of retinal neurons. TH is known to induce differentiation and patterning of cone photoreceptors. However, the mechanisms of induction are not yet established. In addition, the role of TH in other neural retinal cell types, such as bipolar horizontal and amacrine cells, is unknown. The objective of this proposal is to identify thyroid hormone receptor beta2 (Tr[unreadable]2)-regulated pathways involved in differentiation and function of cone photoreceptor. Using the human retinoblastoma cell line WERI as a model of cone photoreceptors, we discovered that thyroid hormone dramatically induces expression of the red (L, for long-wave-sensitive) and green (M, for middle-wave sensitive) but not blue (S, for short-wave-sensitive) pigment genes. We also found in WERI cells that TH regulates a number of other genes that are known to be involved in photoreceptor function, as well as others that are not yet known to be involved in cone differentiation and function (1). We will identify in vivo, using a mouse model, all the genes that are regulated by TH, via Tr[unreadable]2, during various stages of retinal development by mRNA microarray analysis. The proposed mouse model is a Tr[unreadable]2 knockout mouse, that generates S- but not M-cones), on the genetic background of the nuclear retina leucine zipper transcription factor (Nrl) knockout. Nrl is necessary for rod differentiation and the knockout has cones instead of rods in the retina. This model would be necessary to yield enough cone-specific mRNA for gene expression analysis during development. We will compare retinal mRNA expression between Nrl knockout and Nrl/Tr[unreadable]2 double knockout mouse models by microarray analysis of retinal mRNA. This will identify the downstream target genes of TH/TR[unreadable]2 in cones during development. Subsequently, we will determine their temporal and spatial patterns of expression during retinal development. The results of these studies will provide new insights into the pathways and molecular mechanisms involved in establishment of the cone photoreceptor mosaic and color vision. Selective Tr[unreadable]2 ligands could potentially be designed to correct abnormal phenotypes during retinal development.